Cognitive disorders have many components including forgetfulness, confusion, memory loss, attentional deficits, and deficits in visual perception. Some of the symptoms of cognitive disorders are associated with decreased levels of the neurotransmitter, acetylcholine. Neurological illnesses related to cholinergic deficiency include presenile dementia and senile dementia of the Alzheimer's type (SDAT), Parkinson's disease, Downe's Syndrome, and dementia pugilistica.
The "cholinergic hypothesis" [R. T. Bartus, et al., Science, 217, 408-417 (Jul. 30, 1982)] suggests that memory loss due to decreased levels of acetylcholine can be ameliorated by correcting the levels of acetylcholine in the brain using an acetylcholine releasing agent, an acetylcholine esterase inhibitor, or by using a drug which mimics acetylcholine (cholinomimetic). Marketing of the acetylcholine esterase inhibitor, tactine, has demonstrated that improvement in memory can be shown in patients with mild to moderate Alzheimer's Disease [M. Williams, Curr. Opin. Invest. Drugs, 2(5), 541-544 (May 1993) ]. The utility of this drug is limited, however, because of adverse side effects especially at the higher doses where it is most effective. Clinical studies using the natural alkaloid, arecoline, a cholinergic agonist, have also demonstrated memory improvement in patients with mild to moderate Alzheimer's Disease. Because of the short half-life of arecoline, the clinical study was done using continuous infusion of the drug over a 2 week period. In addition, a peripheral muscarinic antagonist, N-methylscopolamine, was also administered during the study to prevent potential autonomic side effects. [T. T. Soncrant et al., Psychopharmacology, 112, 421-427 (1993)].
Cholinergic receptors which bind to and are activated by the alkaloid, muscarine, are called muscarinic receptors. Three pharmacologically defined subtypes of muscarinic receptors have been identified. They are referred to as M1, M2, and M3 based upon their affinity for the M1 antagonist, pirenzepine, the M2 antagonist, AFDX- 116, and the M3 antagonist, 4-[(diphenylacetyl)oxy]-1,1-dimethylpiperidinium iodide (4-DAMP). Five different human muscarinic receptors have been cloned. The Hm1 (human m1) receptor is found primarily in the frontal cortex. [T. I. Bonner, Trends in Pharmacological Sciences, supplement, July 20-27 (1989) p11-15,]. Activation of the m1 receptor results in an increase in phosphoinositol hydrolysis (PI turnover).[K. Fukuda, et al. , Ibid,. p. 4-10]. Carbachol, like muscarine, is able to fully activate m1 receptors. These two compounds, however, contain a quaternary ammonium group and as a result are not able to enter the CNS.
U.S. Pat. No. 4,996,201 discloses a group of centrally active muscarinic agents useful as analgesic agents, sleep aids, treating the symptoms of senile dementia. Compound (II) is disclosed as an example of an analogue of oxotremorine. ##STR2##
U.S. Pat. No. 4,937,239 discloses some oximinocarbamates as having muscarinic activity.
European Patent Application 0 257 741 discloses exo-1-azabicyclo[3.3.1]non-3-yl-N-methylcarbamate in Example 11, exo-1-azabicyclo[3.2.1oct-6-yl-N-methylcarbamate in Example 20 and exo-1-azabicyclo[3.3.1]non-3-yl-N,N-dimethylcarbamate in Example 24 as having muscarinic activity.